Allergy is a major health problem in countries with a Western lifestyle. Furthermore, the prevalence of allergic disease is increasing in these countries. Although allergy in general may not be considered a life-threatening disease, asthma annually causes a significant number of deaths. An exceptional prevalence of about 30% of teenagers conveys a substantial loss in quality of life, working days and money, and warrants a classification among major health problems in the Western world.
Clinical allergy manifestation and symptoms are several and may vary depending on the sensitized individual and the allergy inflicted. Common are symptoms like edema, itching, redness and running of the eyes and nose (rhinitis and conjunctivitis) and symptoms from upper and lower airway like wheezing, coughing, shortness of breath, skin conditions like eczema, urticaria and itching. Other symptoms like fatigue are also experienced. Symptomatic treatment aims at reducing or affecting severity of the symptoms or reducing the need for other drugs given in parallel. Symptomatic drugs include antihistamines like H1 and H2 receptor antagonists, intranasal and systemic corticosteroids, non-steroid anti-inflammatory drugs, nasal decongestants like adrenoceptor agonists. Treatment and relief of one or more allergic symptom and/or the reduction in the need for other medication is a further object of this invention.
Symptomatic drugs are safe and efficient; however, they do not alter the natural cause of the disease, and they do not control the disease dissemination. A therapeutic alternative is specific allergy vaccination that in most cases reduces or alleviates the allergic symptoms caused by the allergen in question.
Conventional specific allergy vaccination (desensitization) is a causal treatment for allergic disease. It interferes with basic immunological mechanisms resulting in persistent improvement of the patients' immune status. Thus, the protective effect of specific allergy vaccination extends beyond the treatment period in contrast to symptomatic drug treatment. Some patients receiving the treatment are cured, and in addition, most patients experience a relief in disease severity and symptoms experienced, or at least an arrest in disease aggravation. Thus, specific allergy vaccination has preventive effects reducing the risk of hay fever developing into asthma, and reducing the risk of developing new sensitivities.
Conventional specific allergy vaccination or desensitisation is carried out using multiple subcutaneous immunizations with allergen (also called SCIT, SIT or subcutaneous immunotherapy) applied over an extended time period. The course is divided in two phases, the up dosing and the maintenance phase. In the up dosing phase increasing doses of allergen are applied, typically over a 16-week period, starting with minute doses. When the recommended maintenance dose is reached, this dose of allergen is applied for the maintenance phase, typically with injections every six weeks. Following each injection the patient must remain under medical attendance for 30 minutes due to the risk of anaphylactic side reactions, which in principle although extremely rare could be life-threatening. In addition, the clinic should be equipped to support emergency treatment.
As allergic individuals are an inhomogeneous group displaying different symptoms and different degrees of severity of their symptoms when exposed to even the same allergen, effective doses may vary. Some patients can tolerate larger doses without experiencing unacceptable side effects, while others are hypersensitive. In some cases escalating doses may be given to reach high dose levels as it is generally believed that larger doses are believed to be more effective doses.
Alutard SQ (Alk-Abello A/S) is a depot formulation in the form of a suspension for subcutaneous injection containing allergens adsorbed to aluminium hydroxide. Alutard SQ has been on the market for many years.
The maintenance dose for Alutard SQ depends on the individual patient and is suitable between 10.000 SQ-U and 100.000 SQ-U given every 4-8 weeks as a subcutaneous injection. To achieve optimal effect the maximal dose of 100.000 SQ-U should be used. However, maintenance doses as low as 10.000 SQ-U has been shown to have some effect, Frew A J, Powell R J, Corrigan C J, Durham S R. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006 February; 117 (2):319-25.
Up-dosing is conventionally carried out to avoid serious adverse effects by allowing patients to gradually become used to higher doses of the allergen.
For Alutard SQ up-dosing may be carried out as shown in table 1 below.
TABLE 1ConcentrationInjectionVolumeDoseVial No.(SQ-U/ml)Week No.No.(ml)(SQ-U)100110.220100220.440100330.88021.000440.22001.000550.44001.000660.8800310.000770.22.00010.000880.44.00010.000990.88.0004100.00010100.110.000100.00011110.220.000100.00012120.440.000100.00013130.660.000100.00014140.880.000100.00015151.0100.000
For Alutard SQ, the recommended interval between each incremental dose in the up-dosing phase is one week. However an interval of up to 14 days is allowed. If more than 14 days has passed since the previous dose, the previous dose is repeated or the dose is reduced.
An 8-step updosing schedule for Alutard SQ has been used for several years in the Scandinavian countries. This up-dosing schedule consists of 8 visits with one week intervals with 2-3 cluster injections during each visit. A maintenance dose of 100.000 SQ-U may thereby be reached in 8 weeks. The dose of 16.000 SQ-U may be reached after 3 visits and a total of 7 injections, Mellerup M T, Hahn G W, Poulsen L K, Mailing H. Safety of allergen-specific immunotherapy, Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment, Clin Exp Allergy 2000 October; 30 (10):1423-9.
Other products such as Pangramin Plus (ALK-Abello SpA) and ALK-7 (ALK-Scherax) allows a maintenance dose of 100.000 SQ-U to be reached in 7 weeks.
Recently it has been described that the maintenance dose in SIT can be reached via incremental doses given over a few consecutive days (ultra-rush SIT) and it is described how the maintenance dose of 100.000 SQ-U was reached on day 3 following subcutaneous injection of an increasing dose of birch allergen during 3 consecutive days, Månsson, A. el al, Ultra-rush specific immunotherapy against birch pollen-induced allergic rhinitis induces alterations in leukocyte phenotype, EAACHI, supplement 88, Volume 63, 2008, abstract 12.
It has now been found that the maintenance dose of a pharmaceutical product comprising allergen may be reached by an up-dosing schedule involving fewer injections. It has also been found that flexible time intervals between each incremental dose in the up-dosing phase may be used. The interval between each incremental dose may be as low as one day and as high as 14 days, which allow the patient to pick and chose the days for the injections in the up-dosing phase more freely than allowed by known up-dosing schedules. The number of injections to reach the maintenance dose may be as low as 5, 4, 3 or 2 injections.
It has also been found that a composition with a reduced dose of allergen (15.000 SQ-U as maintenance dose) compared to the Alutard SQ product may be very effective.
According to the invention the maintenance dose is typically 15.000 SQ-U suitably adsorbed to aluminium hydroxide in an amount corresponding to 0.5 to 0.6 mg aluminum ion, which means that the amount of injected aluminium hydroxide is reduced by 50% compared to the amount injected with a dose of 100.000 SQ-U of Alutard SQ.
The lower amount of aluminium hydroxide in compositions containing aluminium hydroxide as adjuvant will reduce adverse reactions at the injection site due to the aluminium hydroxide and the much lower amount of allergen administered with each injection will reduce the risk adverse reactions such as anaphylactic shock.